A genetic research program is proposed to investigate mammary tumor progression by using mutant mouse models that we have generated by a gene knock-out approach. These null mutations include genes encoding members of the family of insulin-like growth factors (IGFs) and receptors and an early response proto-oncogene (c-fos). Recent evidence demonstrating an involvement of the IGF system in cell transformation and tumorigenesis has provided a strong indication for the proposed genetic analyses. These studies, performed advantageously in the context of the whole experimental organism, have the potential to establish causal relationships between events in the multistep process of mammary carcinogenesis, and are likely to provide information of practical significance for the eventual design of rational therapeutic regimes to treat breast cancer. To initiate our investigation, we have advanced a working hypothesis postulating that tumor development will be prevented or reduced in severity in genetic backgrounds null for signaling pathways regulating growth. Thus, the development of mammary tumors in mice carrying an oncogenic transgene (neu) will be examined in a background null for IGF-II, IGF-I and Fos. Similarly, mice lacking both the tumor suppressor p53 and IGF-ll will also be studied. If certain conditions are met, these studies will be expanded to include null mutations of the genes encoding the type-I IGF and epidermal growth factor receptors (IGFIR and EGFR). In addition, we will generate transgenic animals overexpressing an Igflr cDNA under the control of the mouse mammary tumor virus LTR, to examine critically the involvement of IGFIR in mammary tumorigenesis, which has been suggested from several published reports. Finally, as a service to the scientific community, we will establish, and make available to breast cancer investigators, cell lines carrying combinations of the studied mutations that will be suitable for a variety of in vitro studies.